Colonic delivery refers to the targeted delivery of drugs into the lower GI tract (i.e., colon) which is advantageous for localized treatment of several colonic diseases, namely inflammatory bowel diseases (Crohn's disease and ulcerative colitis), irritable bowel syndrome, and colon cancer. Other potential applications of colonic delivery include chronotherapy of diseases such as asthma, hypertension, cardiac arrhythmias, arthritis, or inflammation, which are affected by circadian biorhythms, prophylaxis of colon cancer and treatment of nicotine addiction.
The colon also offers an opportunistic site for oral delivery of vaccines because it is rich in lymphoid tissue making possible the uptake of antigens through the colonic mucosa leading to rapid and local production of antibodies. There is also an interest in colonic delivery for improving the oral bioavailability of drugs that are substrates of cytochrome P450 3A. Increasing bioavailability via a colonic formulation approach has also been found to be effective in minimizing unwanted side-effects. Also, for drugs with high first pass hepatic metabolism the colon is an attractive target for delivery into the lymphatic system thus by-passing the liver.
Formulations for colonic delivery are also suitable for delivery of drugs that are polar and/or susceptible to chemical and enzymatic degradation in the upper GI tract, in particular, proteins and peptides, such as insulin, calcitonin, and vasopressin.
However, colonic specific delivery presents numerous challenges due to the physiology of the gastro-intestinal tract. One potential issue is that the colon has a distal location and the GI tract has numerous physiological gradients (e.g., pH, enzymes, absorption barrier, etc). Other issues stem from the large differences in the absorptive surface area of the small intestine (e.g., greater than about 120 m2) and the colon (e.g., about 0.25 m2). In addition to the relatively low surface area, there is a limited amount of fluid available for drug dissolution within the colon. Drug stability within the colon remains a problem as numerous drugs have been shown to be metabolised by colonic microbiota and the proteolytic enzymatic activity of the colon is high. Furthermore, there are difficulties designing a precise trigger for drug release within the colon.
Several approaches have been developed to circumvent some of these colonic delivery problems. First approaches utilize enteric coatings on tablets or capsules to bypass the delivery to the stomach; however, the long transit time through the small intestine and lag times at the ileo-cecal junction may prevent accurate release of enterically coated drug formulations. Another approach has been to utilize time dependent release systems with swellable methyl cellulose coatings. These colonic delivery systems can be problematic due to variable gastric release times and rapid transit due to frequent diarrhea in patients with inflammatory bowel disease (IBD).
More integrated approaches have been developed, for example, U.S. Pat. No. 4,190,176 describes an Azo-prodrug system for colonic delivery. The Azo moeity reduces the absorption of the drug in the small intestine. Release within the colon relies upon bacterially produced enzymes which cleave the Azo linkage of the prodrug, allowing it to be absorbed. Other chemical linkages have been used, including amide linkages, glycosidic linkages, and glucoronide linkages. However, this approach can be limiting as the drug/prodrug formulation is highly dependent upon available functional groups on the drug for chemical linkage and prodrugs are new chemical entities requiring time-consuming in vivo evaluation. A similar approach described in U.S. Pat. No. 6,506,407 uses bacterially initiated degradation of a polysaccharide and subsequent localized pH changes for degradation of an enteric polymer coating.
Another approach described in U.S. Pat. No. 5,637,319 for colonic drug delivery is because the colon can exhibit higher pressures on capsules due to peristalsis and increased friction due to lower moisture compared to the small intestine. These type of pressure controlled drug-delivery system utilizes capsules coated with a water-insoluble polymer that prevent drug release in the stomach and small intestine; once the large intestine is reached, the increased pressure results in the breakdown of the capsule. This pressure based strategy can be limiting due to increased drug release lag times, and the dependency of a functional colon (e.g., specifically needed pressures and moisture contents). These systems are limited, as discussed above, in patients with diarrhea or gastro-intestinal problems, especially those patients having IBD.
U.S. Pat. Nos. 4,693,895 and 4,904,474 describe a complex osmotic pressure release system consisting of a hard gelatin capsule comprising an active ingredient in multiple enterically coated subunits for colonic delivery.
Most all of these systems rely on enterically coated tablets or capsules to bypass the stomach, which are produced by a film-coating process, where a thin film layer of acid-insoluble (enteric) polymer is accumulated on the surface of a pre-manufactured dosage form. The enteric coating method involves the spraying of an aqueous or organic solution or a suspension of enteric polymers onto tumbling or moving tablets or capsules, accompanied by drying using hot air.
Enteric dosage forms made by coating suffer from various process-related problems and defects that affect their performance or appearance. For example, “orange peel” surface formation, also known as surface roughness, mottling, or lack of surface homogeneity may result. In addition, coat integrity failure may occur, such as in cases of cracking or flaking of the coating. All coatings present inherent problems, including possible uneven distribution of the coating ingredients, which can easily happen under the multivariate coating process. These failures of enteric coatings reduce the effectiveness of said coating in preventing painful and often harmful gastric and esophageal disturbances.
The foregoing problems of enteric coatings are shared by all enteric dosage forms such as tablets and capsules. However, the problems faced during coating of capsules are even more critical, due to the delicate and heat sensitive nature of the soft elastic capsule shell. Both hard and soft capsules can easily undergo agglomeration and distortion due to the heat-sensitive shell composition. Moreover, the smoothness and elasticity of the capsule surface make it difficult to form an intact adhering enteric coat without careful sub-coating steps to improve the surface for coating. A further disadvantage of enteric coating for soft capsules is the loss of the normally shiny and clear appearance of capsule gelatin shells. The elegant, clear gelatin shell has been a significant reason for soft capsule popularity and acceptance. In addition to the undesirable surface texture modifications usually caused by coating, most accepted aqueous enteric polymer preparations result in opaque capsules.
These prior approaches for colonic delivery are complex and rely on numerous variables for accurate release (e.g., time, drug chemical modification, enzymatic cleavage, peristaltic pressure, etc.). Furthermore, inconsistencies in enteric polymer coatings as described above can lead to inconsistent drug release and efficacy. Therefore, there is a need for a pharmaceutical composition that can be efficiently manufactured, has the popular characteristics of a clear soft gelatin capsule that can be taken orally, and demonstrates a consistent and robust delivery to the colon.